A Randomized, double-blind, dose ranging clinical trial of intravenous FDY-5301 in acute STEMI patients undergoing primary PCI

Adlam, David; Zarębiński, Maciej; Uren, Neal; Ptaszyński, Paweł; Oldroyd, Keith G.; Munir, Shahzad; Zaman, Azfar; Contractor, Hussain; Kiss, Róbert Gábor; Édes, István; Szachniewicz, Joanna; Nagy, Gergely; García, Mario J.; Tomcsányi, János; Irving, John; Sharp, Andrew; Musiałek, Piotr; Lupkovics, Géza; Shirodaria, C; Selvanayagam, Joseph B.; Quinn, Paulene A.; Ng, Leong L.; Roth, Mark B.; Insko, Michael A; Haber, Ben; Hill, Stephen A.; Siegel, Lori S.; Tulloch, Simon; Channon, Keith M.

doi:10.1016/j.ijcard.2021.11.016

Cited by 5 publications

(14 citation statements)

References 18 publications

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“…The increasing interest is this area, has arisen from reports that I⁻ can reduce HOCl-induced oxidative damage derived from MPO in the presence of H₂O₂ [21], and the detection of iodinated proteins from systems containing activated human neutrophils, in sputum from people with cystic fibrosis and in skin abscesses from people infected with S. aureus [23]. In addition, I⁻ supplementation has been reported to afford protection against ischemia-reperfusion injury in a number of animal models [12][13][14], though the origin of this effect has been ascribed to metabolic changes, rather than effects on peroxidase-mediated reactions. These may however be interlinked as thyroid hormone concentrations are dependent on I⁻ concentrations and the activity of thyroid peroxidase.…”

Section: Discussionmentioning

confidence: 99%

“…Together these data suggest that peroxidase-mediated generation of HOI, and formation of iodinated species, may be relevant in individuals with acute or chronic inflammation, in those with high dietary iodine/iodide/iodinated compound consumption, or following exposure to treatments that elevate I⁻ levels. Data indicate that deliberate elevation of I⁻ is protective in humans in cases of radiation exposure (where oral I⁻ tablets are employed to prevent radioactive I⁻ accumulation), to prevent ischemicreperfusion injury [12][13][14], as a treatment for COVID and other viral diseases (povidone-iodine [71] or I⁻ salts [72]) and sepsis [73].…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, supplementation studies using I⁻ indicate that elevated levels of this anion can minimize biological damage. This includes protection against oxidation of isolated proteins and protein mixtures [11], and amelioration of ischemia-reperfusion injury in mice, rats and pigs [12][13][14]. These effects may arise from modulation of HOCl formation and are based on the assumption that HOI (and HOSCN, when levels of SCN⁻ are increased by supplementation [15][16][17][18]) is less damaging than HOCl.…”

Section: Introductionmentioning

confidence: 99%

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Elevated levels of iodide promote peroxidase-mediated protein iodination and inhibit protein chlorination

Jokumsen,

Huhle,

Hägglund

et al. 2024

Preprint

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At inflammatory sites, immune cells generate oxidants including H₂O₂. Myeloperoxidase (MPO), released by activated leukocytes employs H₂O₂ and halide/pseudohalides to form hypohalous acids that mediate pathogen killing. Hypochlorous acid (HOCl) is a major species formed. Excessive or misplaced HOCl formation damages host tissues with this linked to multiple inflammatory diseases. Previously (Redox Biology, 2020, 28, 101331) we reported that iodide (I⁻) modulates MPO-mediated protein damage by decreasing HOCl generation with concomitant hypoiodous acid (HOI) formation. HOI may however impact on protein structure, so in this study we examined whether and how HOI, from peroxidase/H₂O₂/I⁻ systems+Cl⁻, modifies proteins. Experiments employed MPO and lactoperoxidase (LPO) and multiple proteins (serum albumins, anastellin), with both chemical (intact protein and peptide mass mapping, LC-MS) and structural (SDS-PAGE) changes assessed. LC-MS analyses revealed dose-dependent iodination of anastellin and albumins by LPO/H2O2with increasing I⁻. Incubation of BSA with MPO/H2O2/Cl⁻ revealed modest chlorination (Tyr286, Tyr475, ∼4%) and Met modification. Lower levels of these species, and extensive iodination at specific Tyr and His residues (>20% modification with>10 µM I⁻) were detected with increasing I⁻. Anastellin dimerization was inhibited by increasing I⁻, but less marked changes were observed with albumins. These data confirm that I⁻ competes with Cl⁻ for MPO and is an efficient HOCl scavenger. These processes decrease protein chlorination and oxidation, but result in extensive iodination. This is consistent with published data on the presence of iodinated Tyr on neutrophil proteins. The biological implications of protein iodination relative to chlorination require further clarification.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Elevated levels of iodide promote peroxidase-mediated protein iodination and inhibit protein chlorination

Jokumsen,

Huhle,

Hägglund

et al. 2024

Preprint

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“…26 Protected 100% of baboons from terminal organ failure in a Staphylococcus aureus-induced lethal sepsis model. 16 Sodium iodide-based catalyst/hydrogen peroxide reduction for treating IRI FDY-5301 27 Reduced MI infarct sizes and improved LVEF in a phase 2 clinical trial. 27 Platelet-targeted factor Xa inhibitor/selectively inhibiting coagulation on activated platelets Targ-Tap 28 Reduced bleeding risk.…”

Section: Eliminate the Bad But Keep The Goodmentioning

confidence: 99%

Thromboinflammation and the Role of Platelets

Mack,

Vanden Hoek,

2024

ATVB

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“…FDY-5301 is a drug that contains sodium iodide, which is an inorganic halide and elemental reducing agent that may act as a catalytic anti-peroxidant in the conversion of hydrogen peroxide to water and oxygen [ 155 ]. A pilot study showed that i.v.…”

Section: Ongoing Clinical Trials For Drugs Against Myocardial Iri: Po...mentioning

confidence: 99%

Sex Differences in Therapies against Myocardial Ischemia-Reperfusion Injury: From Basic Science to Clinical Perspectives

Medzikovic,

Azem,

Sun

et al. 2023

Cells

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Mortality from myocardial infarction (MI) has declined over recent decades, which could be attributed in large part to improved treatment methods. Early reperfusion is the cornerstone of current MI treatment. However, reoxygenation via restored blood flow induces further damage to the myocardium, leading to ischemia-reperfusion injury (IRI). While experimental studies overwhelmingly demonstrate that females experience greater functional recovery from MI and decreased severity in the underlying pathophysiological mechanisms, the outcomes of MI with subsequent reperfusion therapy, which is the clinical correlate of myocardial IRI, are generally poorer for women compared with men. Distressingly, women are also reported to benefit less from current guideline-based therapies compared with men. These seemingly contradicting outcomes between experimental and clinical studies show a need for further investigation of sex-based differences in disease pathophysiology, treatment response, and a sex-specific approach in the development of novel therapeutic methods against myocardial IRI. In this literature review, we summarize the current knowledge on sex differences in the underlying pathophysiological mechanisms of myocardial IRI, including the roles of sex hormones and sex chromosomes. Furthermore, we address sex differences in pharmacokinetics, pharmacodynamics, and pharmacogenetics of current drugs prescribed to limit myocardial IRI. Lastly, we highlight ongoing clinical trials assessing novel pharmacological treatments against myocardial IRI and sex differences that may underlie the efficacy of these new therapeutic approaches.

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A Randomized, double-blind, dose ranging clinical trial of intravenous FDY-5301 in acute STEMI patients undergoing primary PCI

Cited by 5 publications

References 18 publications

Elevated levels of iodide promote peroxidase-mediated protein iodination and inhibit protein chlorination

Elevated levels of iodide promote peroxidase-mediated protein iodination and inhibit protein chlorination

Thromboinflammation and the Role of Platelets

Sex Differences in Therapies against Myocardial Ischemia-Reperfusion Injury: From Basic Science to Clinical Perspectives

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